A Hybrid drug which comprises the incorporation of two drug pharmacophores in one single molecule are basically designed to interact with multiple targets or to amplify its effect through action on ...another bio target as one single molecule or to counterbalance the known side effects associated with the other hybrid part. The present review article offers a detailed account of the design strategies employed for the synthesis of anticancer agents via molecular hybridization techniques. Over the years, the researchers have employed this technique to discover some promising chemical architectures displaying significant anticancer profiles. Molecular hybridization as a tool has been particularly utilized for targeting tubulin protein as exemplified through the number of research papers. The microtubule inhibitors such as taxol, colchicine, chalcones, combretasatin, phenstatins and vinca alkaloids have been utilized as one of the functionality of the hybrids and promising results have been obtained in most of the cases with some of the tubulin based hybrids exhibiting anticancer activity at nanomolar level. Linkage with steroids as biological carrier vector for anticancer drugs and the inclusion of pyrrolo 2,1-c 1,4benzodiazepines (PBDs), a family of DNA interactive antitumor antibiotics derived from Streptomyces species in hybrid structure based drug design has also emerged as a potential strategy. Various heteroaryl based hybrids in particular isatin and coumarins have also been designed and reported to posses' remarkable inhibitory potential. Apart from presenting the design strategies, the article also highlights the structure activity relationship along with mechanistic insights revealed during the biological evaluation of the hybrids.
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•Molecular hybridization – concept.•Anticancer hybrids – classification.•Design strategies/rational approaches.•Structure activity relationship.•Mechanistic insights.
Enhancing cyclic nucleotides signaling by inhibition of phosphodiesterases (PDEs) is known to be beneficial in disorders associated with cognitive decline. The present study was designed to ...investigate the effect of vinpocetine (PDE1 inhibitor) on intracerebroventricular (i.c.v.) streptozotocin induced experimental sporadic dementia of Alzheimer's type. Infusion of streptozotocin impaired learning and memory, increased oxidative–nitritive stress and induced cholinergic hypofunction in rats. Chronic treatment with vinpocetine (5, 10 and 20
mg/kg i.p.) for 21
days following first i.c.v. streptozotocin infusion significantly improved learning and memory in Morris water maze and passive avoidance paradigms. Further, vinpocetine significantly reduced the oxidative–nitritive stress, as evidenced by decrease in malondialdehyde (MDA) and nitrite levels, and restored the reduced glutathione (GSH) levels. Significant increase in acetylcholinesterase activity and lactate dehydrogenase levels was observed in the present model indicating cholinergic hypofunction and increase in neuronal cell damage. Chronic treatment with vinpocetine also reduced significantly the increase in acetylcholinesterase activity and lactate dehydrogenase levels indicating restorative capacity of vinpocetine with respect to cholinergic functions and preventing the neuronal damage. The observed beneficial effects of vinpocetine on spatial memory may be due to its ability to favorably modulate cholinergic functions, prevent neuronal cell damage and possibly through its antioxidant mechanism also.
Treatment cost is a major concern for modern medicine in developing countries like India and systematic innovative means to reduce these costs are needed. This article reviews the concept of ...bioenhancers to reduce treatment costs by increasing drug bioavailability. This concept, based on the Ayurvedic system of medicine, works for a wide range of ingested substances, and has been applied to modern drugs, particularly single chemicals. It offers a fine example of the benefit of integrating an ancient system with modern medicine in both theory and practice.
Activated JNK has been reported to be located in nucleus in mild cases of Alzheimer's disease (AD), but is exclusively in cytoplasm in more advanced stages of AD and implicated in its pathogenesis, ...suggesting that activation and re-distribution of JNK correlate with the progress of AD. The present study was designed to investigate the role of JNK in intracerebroventricular streptozotocin (i.c.v. STZ) induced cognitive impairment and oxidative stress. Streptozotocin has been observed to impair learning and memory, increase oxidative–nitritive stress, induce cholinergic hypofunction and neuronal damage in rat brain. Chronic treatment with SP600125 from day 10 to 28 following i.c.v. STZ injections significantly improved spatial memory, attenuate oxidative–nitritive stress. In addition, significant increase in acetylcholinesterase activity and lactate dehydrogenase (LDH) levels was observed in the present model indicating cholinergic hypofunction and increase in neuronal cell damage. Whereas, SP600125 treatment significantly restored acetylcholinesterase activity and reduced LDH levels indicating restorative capacity of SP600125 with respect to cholinergic functions and preventing the neuronal damage. In line with previous report, the current study also supports the potential of JNK inhibition as a possible therapeutic strategy to ameliorate neurodegenerative disorders associated with oxidative stress and cognitive impairment.
Cyclic nucleotides viz cGMP and cAMP are known to play an important role in learning and memory processes. Enhancement of cyclic nucleotide signalling through inhibition of phosphodiesterases (PDEs) ...has been reported to be beneficial in several neurodegenerative disorders associated with cognitive decline. The present study was undertaken to investigate the effect of RO-20-1724-a PDE4 inhibitor on streptozotocin (STZ) induced experimental sporadic dementia of Alzheimer's type. The STZ was injected twice intracerebroventrically (3mg/kg i.c.v.) on alternate days (day 1 and day 3) in rats. The STZ injected rats were treated with RO-20-1724 (125, 250 and 500μg/kgi.p.) for 21days following first i.c.v. STZ administration. Learning and memory in rats were assessed by passive avoidance PA (days 14 and 15) and Morris water maze MWM (days 17, 18, 19, 20 and 21) following first i.c.v. STZ administration. On day 22 rat cerebral homogenate was used for all the biochemical estimations. The pharmacological inhibition of PDE4 by RO-20-1724 significantly attenuated STZ induced cognitive deficit and oxidative stress. RO-20-1724 was found to not only improve learning and memory in MWM and PA paradigms but also restore STZ induced elevation in cholinesterase activity. Further, RO-20-1724 significantly reduced malondialdehyde and nitrite levels, and restored the glutathione levels indicating attenuation of oxidative stress. Current data complement previous studies by providing evidence for a subset of cognition enhancing effects after PDE4 inhibition. The observed beneficial effects of RO-20-1724 in spatial memory may be due to its ability to restore cholinergic functions and possibly through its antioxidant mechanisms.
► Effect of PDE4 inhibition against streptozotocin (STZ) induced neurotoxicity. ► STZ produced cognitive dysfunction and increased oxidative stress in rats. ► RO-20-1724, a PDE4 inhibitor, attenuated STZ-induced neurotoxicity. ► PDE4 inhibition may be useful strategy to treat neurodegenerative disorders.
In the last three decades, numerous biopolymeric fractions have been isolated from medicinal plants and used as a source of therapeutic agents. The most promising biopharmacological activities of ...these biopolymers are their immunomodulatory effects. The biopolymeric fraction RLJ-NE-205 was isolated and purified from the rhizomes of
Picrorhiza kurroa. We evaluated the effects of biopolymeric fraction RLJ-NE-205 from
P. kurroa on the in vivo immune function of the mouse. Balb/c mice were treated with the biopolymeric fraction RLJ-NE-205 (12.5, 25 and 50 mg/kg body weight) for 14 days with sheep red blood cells (SRBC) as an antigen. Haemagglutination antibody (HA) titre, plaque forming cell (PFC) assay, delayed type hypersensitivity (DTH) reaction, phagocytic index, proliferation of lymphocytes, analysis of cytokines in serum and CD4/CD8 population in spleen (determined by flowcytometry) were studied. At the dose of 50 mg/kg, significant increases in the proliferation of lymphocytes (
p
<
0.001) and cytokine levels (IL-4 and IFN-gamma) in serum (
p
<
0.001) were observed. A dose dependent increase was demonstrated in HA titre (
p
<
0.05), DTH (
p
<
0.01), PFC (
p
<
0.05), phagocytic index (
p
<
0.05) and CD4/CD8 (
p
<
0.01) population. This suggests that the biopolymeric fraction RLJ-NE-205 improves the immune system and might be regarded as a biological response modifier.
Frozen sections have been used for evaluating tumors and margins during daily practice in pathology with high specificity and sensitivity (>90% for both indices both at national level and in our ...department). The correlation between frozen section tissue for immunofluorescent (IF) studies and permanent sections for light microscopy, along with electron microscopy, is critical for constructing a final renal pathology diagnosis.
We studied the correlation between the frozen sections for IF studies and separate fragments of tissue for permanent light microscopic sections in our renal transplant biopsies for purposes of quality control. Frozen sections for IF sections were compared with permanent sections for light microscopy in 122 renal transplant biopsies, using inflammation as the key criterion (63 with no inflammation and 59 with inflammation) to determine the correlation.
There was high sensitivity (94.9%) and specificity (92.1%) for the correlation between the frozen section and permanent sections.
Our data suggest that parts of renal transplant biopsy tissue dissected to freeze for IF studies and for light microscopy were highly correlated to ensure a high quality of renal tissue dissection for the final diagnosis in renal transplant biopsies.
Peppers are common food ingredients used worldwide. They are also added in traditional antidiarrhoeal formulations of different herbs. Piperine (1) is an alkaloidal constituent of black and long ...peppers recently established as a bioavailability enhancer of drugs and other substances. As a part of efforts to study its effects on the gastrointestinal tract, the experiments were performed to determine the rationale, if any, for its use in traditional antidiarrhoeal formulations. Antidiarrhoeal activity of 1 against castor oil, MgSO4 and arachidonic acid was studied in mice. It significantly inhibited diarrhoea produced by these cathartics at 8 and 32 mg/kg p.o. dose. Inhibition of castor oil induced enteropooling by 1 suggests its inhibitory effect on prostaglandins. The results validate the rationale for its use in traditional antidiarrhoeal formulations.
HP-1 a herbal formulation comprising of Phyllanthus niruri and extracts of Terminalia belerica, Terminalia chebula, Phyllanthus emblica and Tinospora cordifoliahas been evaluated for hepatoprotective ...activity against carbon tetrachloride (CCl4) induced toxicity. Results show that HP-1 reversed the leakage of lactate dehydrogenase (LDH) and glutamate pyruvate transaminase (GPT) and prevented the depletion of glutathione (GSH) levels in a primary monolayer culture of rat hepatocytes (in vitro). HP-1 attenuated the serum toxicity as manifested in elevated levels of transaminases (glutamate oxaloacetate transaminase (GOT), and GPT) The anti-oxidative enzymes in liver (catalase and superoxide dismutase (SOD)) were restored to normal values after the oral administration of HP-1. HP-1 suppressed the formation of the superoxide anion radical and reduced CCl4 mediated lipid peroxidation (LPO). Silymarin and antioxidants (ascorbic acid,β-carotene and tocopherol) were used for comparison. The present study showed that HP-1 is a potential hepatoprotective formulation with an additional attribute of being anti-peroxidative.
Piperine, a major alkaloid of
Piper longum and
Piper nigrum has been reported to have several pharmacological/toxicological effects. Though a number of methods for analysis of this omnipresent food ...component in pepper fruits are available, its analysis in body fluids has been largely neglected. A high-performance liquid chromatography method for the analysis of piperine in rat plasma is presented in this communication. Analysis was performed using a Symmetry
® C
18 column (250×4.6 mm) by isocratic elution with 25 m
M KH
2PO
4 (pH 4.5)–acetonitrile (35:65) and UV detection at 340 nm. The calibration plot was linear over the range studied (2–2000 ng) with correlation coefficient of 0.9984. Limit of detection and limit of quantitation were 1 ng/ml and 3 ng/ml, respectively. Good overall recovery (85.5±6%) was obtained with 4 ml ethyl acetate and extraction time of 3 min. Intra- and inter-assay coefficient of variation was found to be less than 7.5%. Plasma concentration–time profile of piperine in a conscious rat implanted with jugular vein cannula was obtained using this method. The method is simple, sensitive and reproducible.
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